Pathogenic <i>SATB2</i> missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes

<i>SATB2</i>-associated syndrome (SAS) is caused by pathogenic variants in <i>SATB2</i>, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with <i>SATB2</i> variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative <i>SATB2</i> missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.

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Publication Details

Journal
Journal of Medical Genetics
Published
2024-09-26
DOI
https://doi.org/10.1136/jmg-2024-110015
Citations
3
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.70

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article

Pathogenic SATB2 missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes

Lauren Chad, Mubeen Khan, Joery den Hoed, H Hashimoto et al.
3 citations
Journal of Medical Genetics
Epigenetics and DNA Methylation
0.70
article

Pathogenic SATB2 missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes

Lauren Chad, Mubeen Khan, Joery den Hoed, H Hashimoto, Yuri A. Zárate, Eiji Nakagawa, Shinya Yamamoto, Nada Quercia, Chihiro Abe‐Hatano, Hanka Venselaar, Hiroshi Kurosaka, Simon E. Fisher, Katherine A. Bosanko, Stéphane Rondeau, Fleur Semmekrot
article en
3 citations

Abstract

<i>SATB2</i>-associated syndrome (SAS) is caused by pathogenic variants in <i>SATB2</i>, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with <i>SATB2</i> variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative <i>SATB2</i> missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.

Journal of Medical GeneticsVol. 61(11)
University of Kentucky (US), Radboud University Nijmegen (NL), Baylor College of Medicine (US), University of Toronto (CA), Hospital for Sick Children (CA), Radboud University Medical Center (NL), Max Planck Institute for Psycholinguistics (NL), National Center of Neurology and Psychiatry (JP), Neurological Research Institute (US), Centre Hospitalier Universitaire de Rouen (FR), Université de Rouen Normandie (FR), University of Arkansas for Medical Sciences (US), The University of Osaka (JP)
Baylor College of Medicine, Max-Planck-Gesellschaft
Good health and well-being
Openalex Percentile: Top 30%
Epigenetics and DNA Methylation
0.70
DOIOpen Access PDFOpenAlex
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